|“Montaigne concludes, like Socrates, that ignorance aware of itself is the only true knowledge” – from “Forbidden Knowledge” by Roger Shattuck|
A useful review of the history of the anti-vaccination movement: Poland & Jacobson 2011. The Age-Old Struggle against the Antivaccinationists NEJM
Science educators and those who aim to explain the implications of scientific or clinical observations to the public have their work cut out for them. In large part, this is because helping others, including the diverse population of health care providers and their clients, depends upon more than just critical thinking skills. Equally important is what might be termed “disciplinary literacy,” the ability to evaluate whether the methods applied are adequate and appropriate and so whether a particular observation is relevant to or able to resolve a specific question. To illustrate this point, I consider an essay from 1926 by Peter Frandsen and a 2021 paper by Ou et al. (2021) on the mechanism of hydroxychloroquine inhibition of SARS-CoV-2 replication in tissue culture cells.
In Frandsen’s essay, well before the proliferation of unfettered web-based social pontification and ideologically-motivated distortions, he notes that “pseudo and unscientific cults are springing up and finding it easy to get a hold on the popular mind,” and “are making some headway in establishing themselves on an equally recognized basis with scientific medicine,” in part due to their ability to lobby politicians to exclude them from any semblance of “truth in advertising.” Of particular resonance were the efforts in Minnesota, California, and Montana to oppose mandatory vaccination for smallpox. Given these successful anti-vax efforts, Frandsen asks, “is it any wonder that smallpox is one thousand times more prevalent in Montana than in Massachusetts in proportion to population?” One cannot help but analogize to today’s COVID-19 statistics on the dramatically higher rate of hospitalization for the unvaccinated (e.g. Scobie et al., 2021). The comparison is all the more impactful (and disheartening) given the severity of smallpox as a disease, its elimination, in 1977, together with the near elimination of other dangerous viral human diseases (poliomyelitis and measles) primarily via vaccination efforts (Hopkins, 2013), and the discouraging number of high profile celebrities, some of whom I for one previously considered admirable figures (various forms of influencers in modern parlance) who actively promulgate positions that directly contradict objective and reproducible observation and embrace blatantly scientifically untenable beliefs (the vaccine-autism link serves as a prime example).
While much is made of the idea that education-based improvements in critical thinking ability can render its practitioners less susceptible to unwarranted conspiracy theories and beliefs (Lantian et al., 2021), the situation becomes more complex when we consider how it is that presumably highly educated practitioners, e.g. medical doctors, can become conspiracists (ignoring for the moment the more banal, and likely universal, reasons associated with greed and the need to draw attention to themselves). As noted, many is the conspiracist who considers themselves to be a “critical freethinker” (see Lantian et al). The fact that they fail to recognize the flaws in their own thinking leads us to ask, what are they missing?
A point rarely considered is what we might term “disciplinary literacy.” That is, do the members of an audience have the background information necessary to question foundational presumptions associated with an observation? Here I draw on personal experience. I have (an increasingly historical) interest in the interactions between intermediate filaments and viral infection (Doedens et al., 1994; Murti et al., 1988). In 2020, I found myself involved quite superficially with studies by colleagues here at the University of Colorado Boulder; they reproduced the ability of hydroxychloroquine to inhibit coronavirus replication in cultured cells. Nevertheless, and in the face of various distortions, it quickly became apparent that hydroxychloroquine was ineffective for treating SARS-CoV-2 infection in humans. So, what disciplinary facts did one need to understand this apparent contradiction (which appears to have fueled unreasonable advocacy of hydroxychloroquine treatment for COVID)? The paper by Ou et al. (2021) provides a plausible mechanistic explanation. The process of in vitro infection of various cells appears to involve endocytosis followed by proteolytic events leading to the subsequent movement of viral nucleic acid into the cytoplasm, a prerequisite for viral replication. Hydroxychloroquine treatment acts by blocking the acidification of the endosome, which inhibits the capsid cleavage reaction and the subsequent cytoplasmic transport of the virus’s nucleic acid genome (see figure 1, Ou et al. 2021). In contrast, in vivo infection involves a surface protease, rather than endocytosis, and is therefore independent of endosomal acidification. Without a (disciplinary) understanding of the various mechanisms involve in viral entry, and their relevance in various experimental contexts, it remains a mystery for why hydroxychloroquine treatment blocks viral replication in one system (in vitro cultured cells) and not another (in vivo).
In the context of science education and how it can be made more effective, it appears that helping students understand underlying cellular processes, experimental details, and their often substantial impact on observed outcomes is central. This is in contrast to the common focus (in many courses) on the memorization of largely irrelevant details. Understanding how one can be led astray by the differences between experimental systems (and inadequate sample sizes) is essential. One cannot help but think of how mouse studies on diseases such as sepsis (Kolata, 2013) and Alzheimer’s (Reardon, 2018) have been haunted by the assumption that systems that differ in physiologically significant details are good models for human disease and the development of effective treatments. Helping students understand how we come to evaluate observations and the molecular and physiological mechanisms involved should be the primary focus of a modern education in the biological sciences, since it helps build up the disciplinary literacy needed to distinguish reasoned argument from anti-scientific propaganda.
Acknowledgement: Thanks to Qing Yang for bringing the Ou et al paper to my attention.
Shattuck, R. (1996). Forbidden knowledge: from Prometheus to pornography. New York: St. Martin’s Press.
Doedens, J., Maynell, L. A., Klymkowsky, M. W. and Kirkegaard, K. (1994). Secretory pathway function, but not cytoskeletal integrity, is required in poliovirus infection. Arch Virol. suppl. 9, 159-172.
Hopkins, D. R. (2013). Disease eradication. New England Journal of Medicine 368, 54-63.
Kolata, G. (2013). Mice fall short as test subjects for some of humans’ deadly ills. New York Times 11, 467-477.
Lantian, A., Bagneux, V., Delouvée, S. and Gauvrit, N. (2021). Maybe a free thinker but not a critical one: High conspiracy belief is associated with low critical thinking ability. Applied Cognitive Psychology 35, 674-684.
Murti, K. G., Goorha, R. and Klymkowsky, M. W. (1988). A functional role for intermediate filaments in the formation of frog virus 3 assembly sites. Virology 162, 264-269.
Ou, T., Mou, H., Zhang, L., Ojha, A., Choe, H. and Farzan, M. (2021). Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2. PLoS pathogens 17, e1009212.
Reardon, S. (2018). Frustrated Alzheimer’s researchers seek better lab mice. Nature 563, 611-613.
Scobie, H. M., Johnson, A. G., Suthar, A. B., Severson, R., Alden, N. B., Balter, S., Bertolino, D., Blythe, D., Brady, S. and Cadwell, B. (2021). Monitoring incidence of covid-19 cases, hospitalizations, and deaths, by vaccination status—13 US jurisdictions, April 4–July 17, 2021. Morbidity and Mortality Weekly Report 70, 1284.
A recent article in the Guardian reports on a debate at University College London (1) on whether to rename buildings because the people honored harbored odious ideological and political positions. Similar debates and decisions, in some cases involving unacceptable and abusive behaviors rather than ideological positions, have occurred at a number of institutions (see Calhoun at Yale, Sackler in NYC, James Watson at Cold Spring Harbor, Tim Hunt at the MRC, and sexual predators within the National Academy of Sciences). These debates raise important and sometimes troubling issues.
When a building is named after a scientist, it is generally in order to honor that person’s scientific contributions. The scientist’s ideological opinions are rarely considered explicitly, although they may influence the decision at the time. In general, scientific contributions are timeless in that they represent important steps in the evolution of a discipline, often by establishing a key observation, idea, or conceptual framework upon which subsequent progress is based – they are historically important. In this sense, whether a scientific contribution was correct (as we currently understand the natural world) is less critical than what that contribution led to. The contribution marks a milestone or a turning point in a discipline, understanding that the efforts of many underlie disciplinary progress and that those contributors made it possible for others to “see further.” (2)
Since science is not about recognizing or establishing a single unchanging capital-T-Truth, but rather about developing an increasingly accurate model for how the world works, it is constantly evolving and open to revision. Working scientists are not particularly upset when new observations lead to revisions to or the abandonment of ideas or the addition of new terms to equations.(3)
Compare that to the situation in the ideological, political, or religious realms. A new translation or interpretation of a sacred text can provoke schism and remarkably violent responses between respective groups of believers. The closer the groups are to one another, the more horrific the levels of violence that emerge often are. In contrast, over the long term, scientific schools of thought resolve, often merging with one another to form unified disciplines. From my own perspective, and not withstanding the temptation to generate new sub-disciplines (in part in response to funding factors), all of the life sciences have collapsed into a unified evolutionary/molecular framework. All scientific disciplines tend to become, over time, consistent with, although not necessarily deducible from, one another, particularly when the discipline respects and retains connections to the real (observable) world.(4) How different from the political and ideological.
The historical progression of scientific ideas is dramatically different from that of political, religious, or social mores. No matter what some might claim, the modern quantum mechanical view of the atom bears little meaningful similarity to the ideas of the cohort that included Leucippus and Democritus. There is progress in science. In contrast, various belief systems rarely abandon their basic premises. A politically right- or left-wing ideologue might well find kindred spirits in the ancient world. There were genocidal racists, theists, and nationalists in the past and there are genocidal racists, theists, and nationalists now. There were (limited) democracies then, as there are (limited) democracies now; monarchical, oligarchical, and dictatorial political systems then and now; theistic religions then and now. Absolutist ideals of innate human rights, then as now, are routinely sacrificed for a range of mostly self-serving or politically expedient reasons. Advocates of rule by the people repeatedly install repressive dictatorships. The authors of the United States Constitution declare the sacredness of human rights and then legitimized slavery. “The Bible … posits universal brotherhood, then tells Israel to kill all the Amorites.” (Phil Christman). The eugenic movement is a good example; for the promise of a genetically perfect future, existing people are treated inhumanely – just another version of apocalyptic (ends justify the means) thinking.
Ignoring the simpler case of not honoring criminals (sexual and otherwise), most calls for removing names from buildings are based on the odious ideological positions espoused by the honored – typically some version of racist, nationalistic, or sexist ideologies. The complication comes from the fact that people are complex, shaped by the context within which they grow up, their personal histories and the dominant ideological milieu they experienced, as well as their reactions to it. But these ideological positions are not scientific, although a person’s scientific worldview and their ideological positions may be intertwined. The honoree may claim that science “says” something unambiguous and unarguable, often in an attempt to force others to acquiesce to their perspective. A modern example would be arguments about whether climate is changing due to anthropogenic factors, a scientific topic, and what to do about it, an economic, political, and perhaps ideological question.(5)
So what to do? To me, the answer seems reasonably obvious – assuming that the person’s contribution was significant enough, we should leave the name in place and use the controversy to consider why they held their objectionable beliefs and more explicitly why they were wrong to claim scientific justification for their ideological (racist / nationalist / sexist / socially prejudiced) positions.(6) Consider explicitly why an archeologist (Flinders Petrie), a naturalist (Francis Galton), a statistician (Karl Pearson), and an advocate for women’s reproductive rights (Marie Stopes) might all support the non-scientific ideology of eugenics and forced sterilization. We can use such situations as a framework within which to delineate the boundaries between the scientific and the ideological.
Understanding this distinction is critical and is one of the primary justifications for why people not necessarily interested in science or science-based careers are often required to take science courses. Yet all too often these courses fail to address the constraints of science, the difference between political and ideological opinions, and the implications of scientific models. I would argue that unless students (and citizens) come to understand what constitutes a scientific idea or conclusion and what reflects a political or ideological position couched in scientific or pseudo-scientific terms, they are not learning what they need to know about science or its place in society. That science is used as a proxy for Truth writ large is deeply misguided. It is much more important to understand how science works than it is to remember the number of phyla or the names of amino acids, the ability to calculate the pH of a solution, or to understand processes going on at the center of a galaxy or the details of a black hole’s behavior. While sometimes harmless, misunderstanding science and how it is used socially can result in traumatic social implications, such as drawing harmful conclusions about individuals from statistical generalizations of populations, avoidable deaths from measles, and the forced “eugenic” sterilization of people deemed defective. We should seek out and embrace opportunities to teach about these issues, even if it means we name buildings after imperfect people.
- The location of some of my post-doc work.
- In the words of Isaac Newton, “If I have seen further than others, it is by standing upon the shoulders of giants.”
- Unless, of course, the ideas and equations being revised or abandoned are one’s own.
- Perhaps the most striking exception occurs in physics on the subjects of quantum mechanics and relativity, but as I am not a physicist, I am not sure about that.
- Perhaps people are “meant” to go extinct.
- The situation is rather different outside of science, because the reality of progress is more problematic and past battles continue to be refought. Given the history of Reconstruction and the Confederate “Lost Cause” movement [see PBS’s Reconstruction] following the American Civil War, monuments to defenders of slavery, no matter how admirable they may have been in terms of personal bravery and such, reek of implied violence, subjugation, and repression, particularly when the person honored went on to found an institution dedicated to racial hatred and violent intimidation [link]. There would seem little doubt that a monument in honor of a Nazi needs to be eliminated and replaced by one to their victims or to those who defeated them.
Michael Reiss, a professor of science education at University College London and an Anglican Priest, suggests that “we need to rethink the way we teach evolution” largely because conventional approaches can be unduly confrontational and “force religious children to choose between their faith and evolution” or to result in students who”refuse to engage with a lesson.” He suggests that a better strategy would be akin to those use to teach a range of “sensitive” subjects “such as sex, pornography, ethnicity, religion, death studies, terrorism, and others” and could “help some students to consider evolution as a possibility who would otherwise not do so.” [link to his original essay and a previous post on teaching evolution: Go ahead and teach the controversy].
There is no doubt that an effective teacher attempts to present materials sensitively; it is the rare person who will listen to someone who “teaches” ideas in a hostile, alienating, or condescending manner. That said, it can be difficult to avoid the disturbing implications of scientific ideas, implications that can be a barrier to their acceptance. The scientific conclusion that males and females are different but basically the same can upset people on various sides of the theo-political spectrum.
In point of fact an effective teacher, a teacher who encourages students to question their long held, or perhaps better put, familial or community beliefs, can cause serious social push-back – Trouble with a capital T. It is difficult to imagine a more effective teacher than Socrates (~470-399 BCE). Socrates “was found guilty of ‘impiety’ and ‘corrupting the young’, sentenced to death” in part because he was an effective teacher (see Socrates was guilty as charged). In a religious and political context, challenging accepted Truths (again with a capital T) can be a crime. In Socrates’ case”Athenians probably genuinely felt that undesirables in their midst had offended Zeus and his fellow deities,” and that, “Socrates, an unconventional thinker who questioned the legitimacy and authority of many of the accepted gods, fitted that bill.”
So we need to ask of scientists and science instructors, does the presentation of a scientific, that is, a naturalistic and non-supernatural, perspective in and of itself represent an insensitivity to those with a super-natural belief system. Here it is worth noting a point made by the philosopher John Gray, that such systems extend beyond those based on a belief in god(s); they include those who believe, with apocalyptic certainty, in any of a number of Truths, ranging from the triumph of a master race, the forced sterilization of the unfit, the dictatorship of the proletariat, to history’s end in a glorious capitalist and technological utopia. Is a science or science instruction that is “sensitive” to, that is, uncritical of or upsetting to those who hold such beliefs, possible?
My original impression is that one’s answer to this question is likely to be determined by whether one considers science a path to Truth, with a purposeful capital T, or rather that the goal of scientists is to build a working understanding of the world around and within us. Working scientists, and particularly biologists who must daily confront the implications of apparently un-intelligent designed organisms (due to ways evolution works) are well aware that absolute certainty is counterproductive. Nevertheless, the proven explanatory and technological power of the scientific enterprise cannot help but reinforce the strong impression that there is some deep link between scientific ideas and the way the world really works. And while some scientists have advocated unscientific speculations (think multiverses and cosmic consciousness), the truth, with a small t, of scientific thinking is all around us.
Photograph of the Milky Way by Tim Carl photography, used by permission
A science-based appreciation of the unimaginable size and age of the universe, taken together with compelling evidence for the relatively recent appearance of humans (Homo sapiens from their metazoan, vertebrate, tetrapod, mammalian, and primate ancestors) cannot help but impact our thinking as to our significance in the grand scheme of things (assuming that there is such a, possibly ineffable, plan)(1). The demonstrably random processes of mutation and the generally ruthless logic by which organisms survive, reproduce, and evolve, can lead even the most optimistic to question whether existence has any real meaning.
Consider, as an example, the potential implications of the progress being made in terms of computer-based artificial intelligence, together with advances in our understanding of the molecular and cellular connection networks that underlie human consciousness and self-consciousness. It is a small step to conclude, implicitly or explicitly, that humans (and all other organisms with a nervous system) are “just” wet machines that can (and perhaps should) be controlled and manipulated. The premise, the “self-evident truth”, that humans should be valued in and of themselves, and that their rights should be respected (2) is eroded by the ability of machines to perform what were previously thought to be exclusively human behaviors.
Humans and their societies have, after all, been around for only a few tens of thousands of years. During this time, human social organizations have passed from small wandering bands influenced by evolutionary kin and group selection processes to produce various social systems, ranging from more or less functional democracies, pseudo-democracies (including our own growing plutocracy), dictatorships, some religion-based, and totalitarian police states. Whether humans have a long term future (compared to the millions of years that dinosaurs dominated life on Earth) remains to be seen – although we can be reasonably sure that the Earth, and many of its non-human inhabitants, will continue to exist and evolve for millions to billions of years, at least until the Sun explodes.
So how do we teach scientific conclusions and their empirical foundations, which combine to argue that science represents how the world really works, without upsetting the most religiously and politically fanatical among us? Those who most vehemently reject scientific thinking because they are the most threatened by its apparently unavoidable implications. The answer is open to debate, but to my mind it involves teaching students (and encouraging the public) to distinguish empirically-based, and so inherently limited observations and the logical, coherent, and testable scientific models they give rise to from unquestionable TRUTH- and revelation-based belief systems. Perhaps we need to focus explicitly on the value of science rather than its “Truth”. To reinforce what science is ultimately for; what justifies society’s support for it, namely to help reduce human suffering and (where it makes sense) to enhance the human experience, goals anchored in the perhaps logically unjustifiable, but nevertheless essential acceptance of the inherent value of each person.
- Apologies to “Good Omens”
- For example, “We hold these truths to be self-evident, that all men are created equal, that they are endowed by their creator with certain unalienable rights, that among these are life, liberty and the pursuit of happiness.”
Most recent post: Avoiding unrecognized racist implications arising from teaching genetics
- Is it possible to teach evolutionary biology “sensitively”? – 10 June 2019.
- Science “awareness” versus “literacy” and why it matters, politically.– 17 May 2019
- On teaching developmental biology in the 21st century – 15 December 2018
- Aggregative and clonal metazoans – 28 December 2018
- Establishing Cellular Asymmetries – 6 January 2019
- Gradients and non-linear responses – 19 January 2019
- On teaching genetics, social evolution & understanding the origins of racism – 17 October 2018
Please note, given the move from PLoS some of the links in the posts may be broken; some minor editing in process. All by Mike Klymkowsky unless otherwise noted
- In an age of rampant narcissism and social cheating – the importance of teaching social evolutionary mechanisms– 22 Dec. 2016
- Recognizing scientific literacy & illiteracy– 16 Oct. 2016
- Biology education in the light of single cell/molecule studies– 30 Oct. 2016
- The pernicious effects of disrespecting the constraints of science– 30 Nov. 2016
- What can the anti-vaccination movement teach us about improving the public’s understanding of science? Jeanne Garbarino – 5 Jan. 2017
- Power posing & science education – 27 Jan. 2017
- From the science march to the classroom: recognizing science in politics and politics in science: Jeanne Garbarino – 20 Mar. 2017
- Science, politics & marches – 10 Apr. 2017
- After the march for science, What Now?: Yoo Jung Kim – 1 May 2017
- Go ahead and “teach the controversy:” it is the best way to defend science – 24 May 2017
- The trivialization of science education – 28 June 2017
- Visualizing and teaching evolution through synteny – 10 July 2017
- Is it time to start worrying about conscious human “mini-brains”? – 1 August 2017
- Reverse Dunning-Kruger effects and their impact on science education – 14 September 2017
- Humanized mice and porcinized people – 30 September 2017
- Balancing research prestige, human decency, and educational outcomes – 19 Nov. 2017
- Making education matter in higher education – 8 December 2017
- Is a little science a dangerous thing – 8 March 2018
- Molecular machines and the place of physics in the biology curriculum – April 20, 2018
- When is a gene product a protein when is it not? – 14 May 2018
- Ideas are easy, theories are hard. – 24 May 2018
- Genes – way weirder than you thought – 9 July 2018
- Can we talk scientifically about free will? – 15 September 2018.
Embryogenesis is based on a framework of social (cell-cell) interactions, initial and early asymmetries, and cascading cell-cell signaling and gene regulatory networks (DEVO posts one, two, & three). The result is the generation of embryonic axes, germ layers (ectoderm, mesoderm, endoderm), various organs and tissues (brains, limbs, kidneys, hearts, and such) and their characteristic cell types, their patterning, and their coordination into a functioning organism. It is well established that all animals share a common ancestor (hundreds of millions of years ago) and that a number of molecular modules were already present in that common ancestor.
At the same time evolutionary processes are, and need to be, flexible enough to generate the great diversity of organisms, with their various adaptations to particular life-styles. The extent of both conservation and flexibility (new genes, new mechanisms) in developmental systems is, however, surprising. Perhaps the most striking evidence for the depth of this conservation was supplied by the discovery of the organization of the Hox gene cluster in the fruit fly Drosophila and in the mouse (and other vertebrates). In both, the Hox genes are arranged and expressed in a common genomic and expression patterns. But as noted by Denis Duboule (2007) Hox gene organization is often presented in textbooks in a distorted manner (↓).
The Hox gene clusters of vertebrates are compact, but are split, disorganized, and even “atomized” in other types of organisms. Similarly, processes that might appear foundational, such as the role of the Bicoid gradient in the early fruit fly embryo (a standard topic in developmental biology textbooks), is in fact restricted to a small subset of flies (Stauber et al., 1999). New genes can be generated through well defined processes, such as gene duplication and divergence, or they can arise de novo out of sequence noise (Carvunis et al., 2012; Zhao et al., 2014 – see Van Oss & Carvunis 2019. De novo gene birth). Comparative genomic analyses can reveal the origins of specific adaptations (see Stauber et al., 1999). The result is that organisms as closely related to each other as the great apes (including humans) have significant species-specific genetic differences (see Florio et al., 2018; McLean et al., 2011; Sassa, 2013 and references therein) as well as common molecular and cellular mechanisms.
A universal (?) feature of developing systems – gradients and non-linear responses: There is a predilection to find (and even more to teach) simple mechanisms that attempt to explain everything (witness the distortion of the Hox cluster, above) – a form of physics “theory of everything” envy. But the historic nature, evolutionary plasticity, and need for regulatory robustness generally lead to complex and idiosyncratic responses in biological systems. Biological systems are not “intelligently designed” but rather cobbled together over time through noise (mutation) and selection (Jacob, 1977)(see blog post).
That said, a common (universal?) developmental process appears to be the transformation of asymmetries into unambiguous cell fate decisions. Such responses are based on threshold events controlled by a range of molecular behaviors, leading to discrete gene expression states. We can approach the question of how such decisions are made from both an abstract and a concrete perspective. Here I outline my initial approach – I plan to introduce organism specific details as needed. I start with the response to a signaling gradient, such as that found in many developmental systems, including the vertebrate spinal cord (top image Briscoe and Small, 2015) and the early Drosophila embryo (Lipshitz, 2009)(↓).
We begin with a gradient in the concentration of a “regulatory molecule” (the regulator). The shape of the gradient depends upon the sites and rates of synthesis, transport away from these sites, and turnover (degradation and/or inactivation). We assume, for simplicity’s sake, that the regulator directly controls the expression of target gene(s). Such a molecule binds in a sequence specific manner to regulatory sites, there could be a few or hundreds, and lead to the activation (or inhibition) of the DNA-dependent, RNA polymerase (polymerase), which generates RNA molecules complementary to one strand of the DNA. Both the binding of the regulator and the polymerase are stochastic processes, driven by diffusion, molecular collisions, and binding interactions.(1)
Let us now consider the response of target gene(s) as a function of cell position within the gradient. We might (naively) expect that the rate of target gene expression would be a simple function of regulator concentration. For an activator, where the gradient is high, target gene expression would be high, where the gradient concentration is low, target gene expression would be low – in between, target gene expression would be proportional to regulator concentration. But generally we find something different, we find that the expression of target genes is non-uniform, that is there are thresholds in the gradient: on one side of the threshold concentration the target gene is completely off (not expressed), while on the other side of the threshold concentration, the target gene is fully on (maximally expressed). The target gene responds as if it is controlled by an on-off switch. How do we understand the molecular basis for this behavior?
Distinct mechanisms are used in different systems, but we will consider a system from the gastrointestinal bacteria E. coli that students may already be familiar with; these are the genes that enable E. coli to digest the mammalian milk sugar lactose. They encode a protein needed to import lactose into a bacterial cell and an enzyme needed to break lactose down so that it can be metabolized. Given the energetic cost to synthesize these proteins, it is in the bacterium’s adaptive self interest to synthesize them only when lactose is present at sufficient concentrations in their environment. The response is functionally similar to that associated with quorum sensing, which is also governed by threshold effects. Similarly cells respond to the concentration of regulator molecules (in a gradient) by turning on specific genes in specific domains, rather than uniformly.
Now let us look in a little more detail at the behavior of the lactose utilization system in E. coli following an analysis by Vilar et al (2003)(2). At an extracellular lactose concentration below the threshold, the system is off. If we increase the extracellular lactose concentration above threshold the system turns on, the lactose permease and β-galactosidase proteins are made and lactose can enter the cell and be broken down to produce metabolizable sugars. By looking at individual cells, we find that they transition, apparently stochastically from off to on (→), but whether they stay on depends upon the extracellular lactose concentration. We can define a concentration, the maintenance concentration, below the threshold, at which “on” cells will remain on, while “off” cells will remain off.
The circuitry of the lactose system is well defined (Jacob and Monod, 1961; Lewis, 2013; Monod et al., 1963)(↓). The lacI gene encodes the lactose operon repressor protein and it is expressed constituately at a low level; it binds to sequences in the lac operon and inhibits transcription. The lac operon itself contains three genes whose expression is regulated by a constituatively active promoter. LacY encodes the permease while the lacZ encodes β-galactosidase. β-galactosidase has two functions: it catalyzes the reaction that transforms lactose into allolactone and it cleaves lactose into the metabolically useful sugars glucose and galactose. Allolactone is an allosteric modulator of the Lac repressor protein; if allolactone is present, it binds to lac epressor proteins and inactivates them, allowing lac operon expression.
The cell normally contains only ~10 lactose repressor proteins. Periodically (stochastically), even in the absence of lactose, and so its derivative allolactone, the lac operon promoter region is free of repressor proteins, and a lactose operon is briefly expressed – a few LacY and LacZ polypeptides are synthesized (↓). This noisy leakiness in the regulation of the lac operon allows the cell to respond if lactose happens to be present – some lactose molecules enter the cell through the permease, are converted to allolactone by β-galactosidase. Allolactone is an allosteric effector of the lac repressor; when present it binds to and inactivates the lac repressor protein so that it no longer binds to its target sequences (the operator or “O” sites). In the absence of repressor binding, the lac operon is expressed. If lactose is not present, the lac operon is inhibited and lacY and LacZ disappear from the cell by turnover or growth associated dilution.
The question of how the threshold concentration for various signal-regulated decisions is set often involves homeostatic processes that oppose the signaling response. The binding and activation of regulators can involve cooperative interactions between molecular components and both positive and negative feedback effects.
In the case of patterning a tissue, in terms of regional responses to a signaling gradient, there can be multiple regulatory thresholds for different genes, as well as indirect effects, where the initiation of gene expression of one set of target genes impacts the sensitive expression of subsequent sets of genes. One widely noted mechanism, known as reaction-diffusion, was suggested by the English mathematician Alan Turing (see Kondo and Miura, 2010) – it postulates a two component system. One component is an activator of gene expression, which in addition to its own various targets, positively regulates its own expression. The second component is a repressor of the first. Both of these two regulator molecules are released by the signaling cell or cells; the repressor diffuses away from the source faster than the activator does. The result can be a domain of target gene expression (where the concentration of activator is sufficient to escape repression), surrounded by a zone in which expression is inhibited (where repressor concentration is sufficient to inhibit the activator). Depending upon the geometry of the system, this can result in discrete regions (dots or stripes) of primary target gene expression (see Sheth et al., 2012). In real systems there are often multiple gradients present; their relative orientations can produce a range of patterns.
The point of all of this, is that when we approach a particular system – we need to consider the mechanisms involved. Typically they are selected to produce desired phenotypes, but also to be robust in the sense that they need to produce the same patterns even if the system in which they occur is subject to perturbations, such as embryo/tissue size (due to differences in cell division / growth rates) and temperature and other environmental variables.
note: figures returned – updated 13 November 2020.
- While stochastic (random) these processes can still be predictable. A classic example involves the decay of an unstable isotope (atom), which is predictable at the population level, but unpredictable at the level of an individual atom. Similarly, in biological systems, the binding and unbinding of molecules to one another, such as a protein transcription regulator to its target DNA sequence is stochastic but can be predictable in a large enough population.
- and presented in biofundamentals ( pages 216-218).
Briscoe & Small (2015). Morphogen rules: design principles of gradient-mediated embryo patterning. Development 142, 3996-4009.
Carvunis et al (2012). Proto-genes and de novo gene birth. Nature 487, 370.
Duboule (2007). The rise and fall of Hox gene clusters. Development 134, 2549-2560.
Florio et al (2018). Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex. eLife 7.
Jacob (1977). Evolution and tinkering. Science 196, 1161-1166.
Jacob & Monod (1961). Genetic regulatory mechanisms in the synthesis of proteins. Journal of Molecular Biology 3, 318-356.
Kondo & Miura (2010). Reaction-diffusion model as a framework for understanding biological pattern formation. Science 329, 1616-1620.
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21st Century DEVO-2 In the first post in this series [link], I introduced the observation that single celled organisms can change their behaviors, often in response to social signals. They can respond to changing environments and can differentiate from one cellular state to the another. Differentiation involves changes in which sets of genes are expressed, which polypeptides and proteins are made [previous post], where the proteins end up within the cell, and which behaviors are displayed by the organism. Differentiation enables individuals to adapt to hostile conditions and to exploit various opportunities.
The ability of individuals to cooperate with one another, through processes such as quorum sensing, enables them to tune their responses so that they are appropriate and useful. Social interactions also makes it possible for them to produce behaviors that would be difficult or impossible for isolated individuals. Once individual organisms learn, evolutionarily, how to cooperate, new opportunities and challenges (cheaters) emerge. There are strategies that can enable an organism to adapt to a wider range of environments, or to become highly specialized to a specific environment, through the production of increasingly complex behaviors. As described previously, many of these cooperative strategies can be adopted by single celled organisms, but others require a level of multicellularity. Multicellularity can be transient – a pragmatic response to specific conditions, or it can be (if we ignore the short time that gametes exist as single cells) permanent, allowing the organism to develop the range of specialized cells types needed to build large, macroscopic organisms with complex and coordinated behaviors. In appears that various forms of multicellularity have arisen independently in a range of lineages (Bonner, 1998; Knoll, 2011). We can divide multicellularity into two distinct types, aggregative and clonal – which we will discuss in turn (1). Aggregative (transient) multicellularity: Once organisms had developed quorum sensing, they can monitor the density of related organisms in their environment and turn or (or off) specific genes (or sets of genes, necessary to produce a specific behavior. While there are many variants, one model for such a behavior is a genetic toggle switch, in which a particular gene (or genes) can be switched on or off in response to environmental signals acting as allosteric regulators of transcription factor proteins (see Gardner et al., 2000). Here is an example of an activity (↓) that we will consider in class to assess our understanding of the molecular processes involved.
One outcome of such a signaling system is to provoke the directional migration of amoeba and their aggregation to form the transient multicellular “slug”. Such behaviors has been observed in a range of normally unicellular organisms (see Hillmann et al., 2018)(↓). The classic example is the cellular slime mold Dictyostelium discoideum (Loomis, 2014). Under normal conditions, these
unicellular amoeboid eukaryotes migrate, eating bacteria and such. In this state, the range of an individual’s movement is restricted to short distances. However when conditions turn hostile, specifically a lack of necessary nitrogen compounds, there is a compelling reason to abandon one environment and migrate to another, more distant that a single-celled organism could reach. This is a behavior that depends upon the presence of a sufficient density (cells/unit volume) of cells that enables them to: 1) recognize one another’s presence (through quorum sensing), 2) find each other through directed (chemotactic) migration, and 3) form a multicellular slug that can go on to differentiate. Upon differentiation about 20% of the cells differentiate (and die), forming a stalk that lifts the other ~80% of the cells into the air. These non-stalk cells (the survivors) differentiate into spore (resistant to drying out) cells that are released into the air where they can be carried to new locations, establishing new populations.
The process of cellular differentiation in D. discoideum has been worked out in molecular detail and involves two distinct signaling systems: the secreted pre-starvation factor (PSF) protein and cyclic AMP (cAMP). PSF is a quorum signaling protein that also serves to activate the cell aggregation and differentiation program (FIG. ↓)
If bacteria, that is food, are present, the activity of PSF is inhibited and cells remain in their single cell state. The key regulator of downstream aggregation and differentiation is the cAMP-dependent protein kinase PKA. In the unicellular state, PKA activity is inhibited by PufA. As PSF increases, while food levels decrease, YakA activity increases, inactivating PufA, leading to increased PKA activity. Active PKA induces the synthesis of two downstream proteins, adenylate cyclase (ACA) and the cAMP receptor (CAR1). ACA catalyzes cAMP synthesis, much of which is secreted from the cell as a signaling molecule. The membrane-bound CAR1 protein acts as a receptor for autocrine (on the cAMP secreting cell) and paracrine (on neighboring cells) signaling. The binding of cAMP to CAR1 leads to further activation of PKA, increasing cAMP synthesis and secretion – a positive feed-back loop. As cAMP levels increase, downstream genes are activated (and inhibited) leading cells to migrate toward one another, their adhesion to form a slug. Once the slug forms and migrates to an appropriate site, the process of differentiation (and death) leading to stalk and spore formation begins. The fates of the aggregated cells is determined stochastically, but social cheaters can arise. Mutations can lead to individuals that avoid becoming stalk cells. In the long run, if all individuals were to become cheaters, it would be impossible to form a stalk, so the purpose of social cooperation would be impossible to achieve. In the face of environmental variation, populations invaded by cheaters are more likely to become extinct. For our purposes the various defenses against cheaters are best left to other courses (see here if interested Strassmann et al., 2000).
Clonal (permanent) multicellularity: The type of multicellularity that most developmental biology courses focus on is what is termed clonal multicellularity – the organism is a clone of an original cell, the zygote, a diploid cell produced by the fusion of sperm and egg, haploid cells formed through the process of meiosis (2). It is during meiosis that most basic genetic processes occur, that is the recombination between maternal and paternal chromosomes leading to the shuffling of alleles along a chromosome, and the independent segregation of chromosomes to form haploid gametes, gametes that are genetically distinct from those present in either parent. Once the zygote forms, subsequent cell divisions involve mitosis, with only a subset of differentiated cells, the cells of the germ line, capable of entering meiosis.
Non-germ line, that is somatic cells, grow and divide. They interact with one another directly and through various signaling processes to produce cells with distinct patterns of gene expression, and so differentiated behaviors. A key difference from a unicellular organism, is that the cells will (largely) stay attached to one another, or to extracellular matrix materials secreted by themselves and their neighbors. The result is ensembles of cells displaying different specializations and behaviors. As such cellular colonies get larger, they face a number of physical constraints – for example, cells are open non-equilibrium systems, to maintain themselves and to grow and reproduce, they need to import matter and energy from the external world. Cells also produce a range of, often toxic, waste products that need to be removed. As the cluster of zygote-derived cells grows larger, and includes more and more cells, some cells will become internal and so cut off from necessary resources. While diffusive processes are often adequate when a cell is bathed in an aqueous solution, they are inadequate for a cell in the interior of a large cell aggregate (3). The limits of diffusive processes necessitate other strategies for resource delivery and waste removal; this includes the formation of tubular vascular systems (such as capillaries, arteries, veins) and contractile systems (hearts and such) to pump fluids through these vessels, as well as cells specialized to process and transport a range of nutrients (such as blood cells). As organisms get larger, their movements require contractile machines (muscle, cartilage, tendons, bones, etc) driving tails, fins, legs, wings, etc. The coordination of such motile systems involves neurons, ganglia, and brains. There is also a need to establish barriers between the insides of an organism and the outside world (skin, pulmonary, and gastrointestinal linings) and the need to protect the interior environment from invading pathogens (the immune system). The process of developing these various systems depends upon controlling patterns of cell growth, division, and specialization (consider the formation of an arm), as well as the controlled elimination of cells (apoptosis), important in morphogenesis (forming fingers from paddle-shaped appendages), the maturation of the immune system (eliminating cells that react against self), and the wiring up, and adaptation of the nervous system. Such changes are analogous to those involved in aggregative multicellularity.
Origins of multicellularity: While aggregative multicellularity involves an extension of quorum sensing and social cooperation between genetically distinct, but related individuals, we can wonder whether similar drivers are responsible for clonal multicellularity. There are a number of imaginable adaptive (evolutionary) drivers but two spring to mind: a way to avoid predators by getting bigger than the predators and as a way to produce varied structures needed to exploit various ecological niches and life styles. An example of the first type of driver of multicellularity is offered by the studies of Boraas et al (1998). They cultured the unicellular green alga Chlorella vulgaris, together with a unicellular predator, the phagotrophic flagellated protist Ochromonas vallescia. After less than 100 generations (cell divisions), they observed the appearance of multicellular, and presumable inedible (or at least less easily edible), forms. Once selected, this trait appears to be stable, such that “colonies retained the eight-celled form indefinitely in continuous culture”. To my knowledge, the genetic basis for this multicellularity remains to be determined.
Cell Differentiation: One feature of simple colonial organisms is that when dissociated into individual cells, each cell is capable of regenerating a new organism. The presence of multiple (closely related) cells in a single colony opens up the possibility of social interactions; this is distinct from the case in aggregative multicellularity, where social cooperation came first. Social cooperation within a clonal metazoan means that most cells “give up” their ability to reproduce a new organism (a process involving meiosis). Such irreversible social interactions mark the transition from a colonial organism to a true multicellular organism. As social integration increases, cells can differentiate so as to perform increasingly specialized functions, functions incompatible with cell division. Think for a moment about a human neuron or skeletal muscle cell – in both cases, cell division is no longer possible (apparently). Nevertheless, the normal functioning of such cells enhances the reproductive success of the organism as a whole – a classic example of inclusive fitness (remember heterocysts?) Modern techniques of single cell sequencing and data analysis have now been employed to map this process of cellular differentiation in increasingly great detail, observations that will inform our later discussions (see Briggs et al., 2018 and future posts). In contrast, the unregulated growth of a cancer cell is an example of an asocial behavior, an asocial behavior that is ultimately futile, except in those rare cases (four known at this point) in which a cancer cell can move from one organism to another (Ujvari et al., 2016).
Unicellular affordances for multicellularity: When considering the design of a developmental biology course, we are faced with the diversity of living organisms – the basic observation that Darwin, Wallace, their progenitors and disciplinary descendants set out to solve. After all there are many millions of different types of organisms; among the multicellular eukaryotes, there are six major group : the ascomycetes and basidiomycetes fungi, the florideophyte red algae, laminarialean brown algae, embryophytic land plants and animals
(Knoll, 2011 ↑). Our focus will be on animals. “All members of Animalia are multicellular, and all are heterotrophs (i.e., they rely directly or indirectly on other organisms for their nourishment). Most ingest food and digest it in an internal cavity.” [Mayer link]. From a macroscopic perspective, most animals have (or had at one time during their development) an anterior to posterior, that is head to tail, axis. Those that can crawl, swim, walk, or fly typically have a dorsal-ventral or back to belly axis, and some have a left-right axis as well.
But to be clear, a discussion of the various types of animals is well beyond the scope of any introductory course in developmental biology, in part because there are 35 (assuming no more are discovered) different “types” (phyla) of animals – nicely illustrated at this website [BBC: 35 types of animals, most of whom are really weird)]. So again, our primary focus will be on one group, the vertebrates – humans are members of this group. We will also consider experimental insights derived from studies of various “model” systems, including organisms from another metazoan group, the ecdysozoa (organisms that shed their outer layer as they grow bigger), a group that includes fruit flies and nematode worms.
My goal will be to ignore most of the specialized terminology found in the scholarly literature, which can rapidly turn a biology course into a vocabulary lesson and that add little to understanding of basic processes relevant to a general understanding of developmental processes (and relevant to human biology, medicine, and biotechnology). This approach is made possible by the discovery that the basic processes associated with animal (and metazoan) development are conserved. In this light, no observation has been more impactful than the discovery that the nature and organization of the genes involved in specifying the head to tail axes of the fruit fly and vertebrates (such as the mouse and human) is extremely similar in terms of genomic organization and function (Lappin et al., 2006 ↓), an observation that we will return to repeatedly. Such molecular similarities extend to cell-cell and cell-matrix adhesion systems, systems that release and respond to various signaling molecules, controlling cell behavior and gene expression, and reflects the evolutionary conservation and the common ancestry of all animals (Brunet and King, 2017; Knoll, 2011).
What can we know about the common ancestor of the animals? Early on in the history of comparative cellular anatomy, the striking structural similarities between the feeding system of choanoflagellate protozoans, a motile (microtubule-based) flagellum a surrounded by a “collar”of microfilament-based microvilli) and a structurally similar organelle in a range of multicellular organisms led to the suggestion that choanoflagellates and animals shared a common ancestor. The advent of genomic sequencing and analysis has only strengthened this hypothesis, namely that choanoflagellates and animals form a unified evolutionary clade, the ‘Choanozoa’ (see tree↑ above)(Brunet and King, 2017). Moreover, “many genes required for animal multicellularity (e.g., tyrosine kinases, cadherins, integrins, and extracellular matrix domains) evolved before animal origins”. The implications is that the Choanozoan ancestor was predisposed to exploit some of the early opportunities offered by clonal multicellularity. These pre-existing affordances, together with newly arising genes and proteins (Long et al., 2013) were exploited in multiple lineages in the generation of multicellular organisms (see Knoll, 2011).
Basically to understand what happened next, some ~600 million years ago or so, we will approach the various processes involved in the shaping of animal development. Because all types of developmental processes, including the unicellular to colonial transition, involve changes in gene expression, we will begin with the factors involved in the regulation of gene expression.
1). Please excuse the inclusive plural, but it seems appropriate in the context of what I hope will be a highly interactive course.
2). I will explicitly ignore variants as (largely) distractions, better suited for more highly specialized courses.
3). We will return to this problem when (late in the course, I think) we will discuss the properties of induced pluripotent stem cell (iPSC) derived organoids.
Bonner, J. T. (1998). The origins of multicellularity. Integrative Biology: Issues, News, and Reviews: Published in Association with The Society for Integrative and Comparative Biology 1, 27-36.
Boraas, M. E., Seale, D. B. and Boxhorn, J. E. (1998). Phagotrophy by a flagellate selects for colonial prey: a possible origin of multicellularity. Evolutionary Ecology 12, 153-164.
Briggs, J. A., Weinreb, C., Wagner, D. E., Megason, S., Peshkin, L., Kirschner, M. W. and Klein, A. M. (2018). The dynamics of gene expression in vertebrate embryogenesis at single-cell resolution. Science 360, eaar5780.
Brunet, T. and King, N. (2017). The origin of animal multicellularity and cell differentiation. Developmental cell 43, 124-140.
Gardner, T. S., Cantor, C. R. and Collins, J. J. (2000). Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339-342.
Hillmann, F., Forbes, G., Novohradská, S., Ferling, I., Riege, K., Groth, M., Westermann, M., Marz, M., Spaller, T. and Winckler, T. (2018). Multiple roots of fruiting body formation in Amoebozoa. Genome biology and evolution 10, 591-606.
Knoll, A. H. (2011). The multiple origins of complex multicellularity. Annual Review of Earth and Planetary Sciences 39, 217-239.
Lappin, T. R., Grier, D. G., Thompson, A. and Halliday, H. L. (2006). HOX genes: seductive science, mysterious mechanisms. The Ulster medical journal 75, 23.
Long, M., VanKuren, N. W., Chen, S. and Vibranovski, M. D. (2013). New gene evolution: little did we know. Annual review of genetics 47, 307-333.
Loomis, W. F. (2014). Cell signaling during development of Dictyostelium. Developmental biology 391, 1-16.
Strassmann, J. E., Zhu, Y. and Queller, D. C. (2000). Altruism and social cheating in the social amoeba Dictyostelium discoideum. Nature 408, 965-967.
Ujvari, B., Gatenby, R. A. and Thomas, F. (2016). Transmissible cancers, are they more common than thought? Evolutionary applications 9, 633-634.
On teaching developmental biology and trying to decide where to start: differentiation
Having considered the content of courses in chemistry  and biology [2, 3], and preparing to teach developmental biology for the first time, I find myself reflecting on how such courses might be better organized. In my department, developmental biology (DEVO) has returned after a hiatus as the final capstone course in our required course sequence, and so offers an opportunity within which to examine what students have mastered as they head into their more specialized (personal) educational choices. Rather than describe the design of the course that I will be teaching, since at this point I am not completely sure what will emerge, what I intend to do (in a series of posts) is to describe, topic by topic, the progression of key concepts, the observations upon which they are based, and the logic behind their inclusion.
Modern developmental biology emerged during the mid-1800s from comparative embryology  and was shaped by the new cell theory (the continuity of life and the fact that all organisms are composed of cells and their products) and the ability of cells to differentiate, that is, to adopt different structures and behaviors . Evolutionary theory was also key. The role of genetic variation based on mutations and selection, in the generation of divergent species from common ancestors, explained why a single, inter-connected Linnaean (hierarchical) classification system (the phylogenic tree of life →) of organisms was possible and suggested that developmental mechanisms were related to similar processes found in their various ancestors.
So then, what exactly are the primary concepts behind developmental biology and how do they emerge from evolutionary, cell, and molecular biology? The concept of “development” applies to any process characterized by directional changes over time. The simplest such process would involve the progress from the end of one cell division event to the beginning of the next; cell division events provide a convenient benchmark. In asexual species, the process is clonal, a single parent gives rise to a genetically identical (except for the occurrence of new mutations) offspring. Often there is little distinction between parent and offspring. In sexual species, a dramatic and unambiguous benchmark involves the generation of a new and genetically distinct organism. This “birth” event is marked by the fusion of two gametes (fertilization) to form a new diploid organism. Typically gametes are produced by a complex cellular differentiation process (gametogenesis), ending with meiosis and the formation of haploid cells. In multicellular organisms, it is often the case that a specific lineage of cells (which reproduce asexually), known as the germ line, produce the gametes. The rest of the organism, the cells that do not produce gametes, is known as the soma, composed of somatic cells. Cellular continuity remains, however, since gametes are living (albeit haploid) cells.
It is common for the gametes that fuse to be of two different types, termed oocyte and sperm. The larger, and generally immotile gamete type is called an oocyte and an individual that produces oocytes is termed female. The smaller, and generally motile gamete type is called a sperm; individuals that produces sperm are termed male. Where a single organism can produce both oocytes and sperm, either at the same time or sequentially, they are referred to as hermaphrodites (named after Greek Gods, the male Hermes and the female Aphrodite). Oocytes and sperm are specialized cells; their formation involves the differential expression of genes and the specific molecular mechanisms that generate the features characteristic of the two cell types. The fusion of gametes, fertilization, leads to a zygote, a diploid cell that (usually) develops into a new, sexually mature organism.
An important feature of the process of fertilization is that it requires a level of social interaction, the two fusing cells (gametes) must recognize and fuse with one another. The organisms that produce these gametes must cooperate; they need to produce gametes at the appropriate time and deliver them in such a way that they can find and recognize each other and avoid “inappropriate” interactions”. The specificity of such interactions underlie the reproductive isolation that distinguishes one species from another. The development of reproductive isolation emerges as an ancestral population of organisms diverges to form one or more new species. As we will see, social interactions, and subsequent evolutionary effects, are common in the biological world.
The cellular and molecular aspects of development involve the processes by which cells grow, replicate their genetic material (DNA replication), divide to form distinct parent-offspring or similar sibling cells, and may alter their morphology (shape), internal organization, motility, and other behaviors, such as the synthesis and secretion of various molecules, and how these cells respond to molecules released by other cells. Developmental processes involve the expression and the control of all of these processes.
Essentially all changes in cellular behavior are associated with changes in the activities of biological molecules and the expression of genes, initiated in response to various external signaling events – fertilization itself is such a signal. These signals set off a cascade of regulatory interactions, often leading to multiple “cell types”, specialized for specific functions (such as muscle contraction, neural and/or hormonal signaling, nutrient transport, processing, and synthesis, etc.). For specific parts of the organism, external or internal signals can result in a short term “adaptive” response (such as sweating or panting in response to increased internal body temperature), after which the system returns to its original state, or in the case of developing systems, to new states, characterized by stable changes in gene expression, cellular morphology, and behavior.
Development in bacteria (and other unicellular organisms): In most unicellular organisms, the cell division process is reasonably uneventful, the cells produced are similar to the original cell – but not always. A well studied example is the bacterium Caulobacter crescentus (and related species) [link][link]. In cases such as this, the process of growth leads to phenotypically different daughters. While it makes no sense to talk about a beginning (given the continuity of life after the appearance of the last universal common ancestor or LUCA), we can start with a “swarmer” cell, characterized by the presence of a motile flagellum (a molecular machine driven by coupled chemical reactions – see past blogpost] that drives motility [figure modified from 6 ↓].
A swarmer will eventually settle down, loose the flagellum, and replace it with a specialized structure (a holdfast) designed to anchor the cell to a solid substrate. As the organism grows, the holdfast develops a stalk that lifts the cell away from the substrate. As growth continues, the end of the cell opposite the holdfast begins to differentiate (becomes different) from the holdfast end of the cell – it begins the process leading to the assembly of a new flagellar apparatus. When reproduction (cell growth, DNA replication, and cell division) occurs, a swarmer cell is released and can swim away and colonize another area, or settle nearby. The holdfast-anchored cell continues to grow, producing new swarmers. This process is based on the inherent asymmetry of the system – the holdfast end of the cell is molecularly distinct from the flagellar end [see 7].
The process of swarmer cell formation in Caulobacter is an example of what we will term deterministic phenotypic switching. Cells can also exploit molecular level noise (stochastic processes) that influence gene expression to generate phenotypic heterogeneity, different behaviors expressed by genetically identical cells within the same environment [see 8, 9]. Molecular noise arises from the random nature of molecular movements and the rather small (compared to macroscopic systems) numbers of most molecules within a cell. Most cells contain one or two copies of any particular gene, and a similarly small number of molecular sequences involved in their regulation . Which molecules are bound to which regulatory sequence, and for how long, is governed by inter-molecular surface interactions and thermally driven collisions, and is inherently noisy. There are strategies that can suppress but not eliminate such noise [see 11]. As dramatically illustrated by Elowitz and colleagues (↑), molecular level noise can produce cells with different phenotypes. Similar processes are active in eukaryotes (including humans), and can lead to the expression of one of the two copies of a gene (mono-allelic expression) present in a diploid organism. This can lead to effects such as haploinsufficiency and selective (evolutionary) lineage effects if the two alleles are not identical [12, 13]. Such phenotypic heterogeneity among what are often genetically identical cells is a topic that is rarely discussed (as far as I can discern) in introductory cell, molecular, or developmental biology courses [past blogpost].
The ability to switch phenotypes can be a valuable trait if an organism’s environment is subject to significant changes. As an example, when the environment gets hostile, some bacterial cells transition from a rapidly dividing to a slow or non-dividing state. Such “spores” can differentiate so as to render them highly resistant to dehydration and other stresses. If changes in environment are very rapid, a population can protect itself by continually having some cells (stochastically) differentiating into spores, while others continue to divide rapidly. Only a few individuals (spores) need to survive a catastrophic environmental change to quickly re-establish the population.
Dying for others – social interactions between “unicellular” organisms: Many students might not predict that one bacterial cell would “sacrifice” itself for the well being of others, but in fact there are a number of examples of this type of self-sacrificing behavior, known as programmed cell death, which is often a stochastic process. An interesting example is provided by cellular specialization for photosynthesis or nitrogen fixation in cyanobacteria [see 9]. These two functions require mutually exclusive cellular environments to occur, in particular the molecular oxygen (O2) released by photosynthesis inhibits the process of nitrogen fixation. Nevertheless, both are required for optimal growth. The solution? some cells differentiate into what are known as heterocysts, cells committed to nitrogen fixation (← a heterocyst in Anabaena spiroides, adapted from link), while most ”vegetative” cells continue with photosynthesis. Heterocysts cannot divide, and eventually die – they sacrifice themselves for the benefit of their neighbors, the vegetative cells, cells that can reproduce.
The process by which the death of an individual can contribute resources that can be used to insure or enhance the survival and reproduction of surrounding individuals is an inherently social process, and is subject of social evolutionary mechanisms [14, 15][past blogpost]. Social behaviors can be selected for because the organism’s neighbors, the beneficiaries of their self-sacrifice are likely to be closely (clonally) related to themselves. One result of the social behavior is, at the population level, an increase in one aspect of evolutionary fitness, termed “inclusive fitness.”
Such social behaviors can enable a subset of the population to survive various forms of environmental stress (see spore formation above). An obvious environmental stress involves the impact of viral infection. Recall that viruses are completely dependent upon the metabolic machinery of the infected cell to replicate. While there are a number of viral strategies, a common one is bacterial lysis – the virus replicates explosively, kills the infected cells, leading to the release of virus into the environment to infect others. But, what if the infected cell kills itself BEFORE the virus replicates – the dying (self-sacrificing, altruistic) cell “kills” the virus (although viruses are not really alive) and stops the spread of the infection. Typically such genetically programmed cell death responses are based on a simple two-part system, involving a long lived toxin and a short-lived anti-toxin. When the cell is stressed, for example early during viral infection, the level of the anti-toxin can fall, leading to the activation of the toxin.
Other types of social behavior and community coordination (quorum effects): Some types of behaviors only make sense when the density of organisms rises above a certain critical level. For example, it would make no sense for an Anabaena cell to differentiate into a heterocyst (see above) if there are no vegetative cells nearby. Similarly, there are processes in which a behavior of a single bacterial cell, such as the synthesis and secretion of a specific enzyme, a specific import or export machine, or the construction of a complex, such as a DNA uptake machine, makes no sense in isolation – the secreted molecule will just diffuse away, and so be ineffective, the molecule to be imported (e.g. lactose) or exported (an antibiotic) may not be present, or there may be no free DNA to import. However, as the concentration (organisms per volume) of bacteria increases, these behaviors can begin to make biological sense – there is DNA to eat or incorporate and the concentration of secreted enzyme can be high enough to degrade the target molecules (so they are inactivated or can be imported as food).
So how does a bacterium determine whether it has neighbors or whether it wants to join a community of similar organisms? After all, it does not have eyes to see. The process used is known as quorum sensing. Each individual synthesizes and secretes a signaling molecule and a receptor protein whose activity is regulated by the binding of the signaling molecule. Species specificity in signaling molecules and receptors insures that organisms of the same kind are talking to one another and not to other, distinct types of organisms that may be in the environment. At low signaling molecule concentrations, such as those produced by a single bacterium in isolation, the receptor is not activated and the cell’s behavior remains unchanged. However, as the concentration of bacteria increases, the concentration of the signal increases, leading to receptor activation. Activation of the receptor can have a number of effects, including increased synthesis of the signal and other changes, such as movement in response to signals through regulation of flagellar and other motility systems, such a system can lead to the directed migration (aggregation) of cells [see 16].
In addition to driving the synthesis of a common good (such as a useful extracellular molecule), social interactions can control processes such as programmed cell death. When the concentration of related neighbors is high, the programmed death of an individual can be beneficial, it can lead to release of nutrients (common goods, including DNA molecules) that can be used by neighbors (relatives)[17, 18] – an increase in the probability of cell death in response to a quorum can increased in a way that increases inclusive fitness. On the other hand, if there are few related individuals in the neighborhood, programmed cell death “wastes” these resources, and so is likely to be suppressed (you might be able to generate a plausible mechanism that could control the probability of programmed cell death).
As we mentioned previously with respect to spore formation, the generation of a certain percentage of “persisters” – individuals that withdraw from active growth and cell division, can enable a population to survive stressful situations, such as the presence of an antibiotic. On the other hand, generating too many persisters may place the population at a reproductive disadvantage. Once the antibiotic is gone, the persisters can return into active division. The ability of bacteria to generate persisters is a serious problem in treating people with infections, particularly those who stop taking their antibiotics too early .
Of course, as in any social system, the presumption of cooperation (expending energy to synthesize the signal, sacrificing oneself for others) can open the system to cheaters [blogpost]. All such “altruistic” behaviors are vulnerable to cheaters.* For example, a cheater that avoids programmed cell death (for example due to an inactivating mutation that effects the toxin molecule involved) will come to take over the population. The downside, for the population, is that if cheaters take over, the population is less likely to survive the environmental events that the social behavior was evolve to address. In response to the realities of cheating, social organisms adopt various social-validation and policing systems [see 20 as an example]; we see this pattern of social cooperation, cheating, and social defense mechanism throughout the biological world.
* Such as people who fail to pay their taxes or disclose their tax returns.
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Links between genetics and race crop up periodically in the popular press (link; link), but the real, substantive question, and the topic of a number of recent essays (see Saletan. 2018a. Stop Talking About Race and IQ) is whether the idea of “race” as commonly understood, and used by governments to categorize people (link), makes scientific sense. More to the point, do biology educators have an unmet responsibility to modify and extend their materials and pedagogical approaches to address the non-scientific, often racist, implications of racial characterizations. Such questions are complicated by a second factor, independent of whether the term race has any useful scientific purpose, namely to help students understand the biological (evolutionary) origins of racism itself, together with the stressors that lead to its periodic re-emergence as a socio-political factor. In times of social stress, reactions to strangers (others) identified by variations in skin color or overt religious or cultural signs (dress), can provoke hostility against those perceived to be members of a different social group. As far as I can tell, few in the biology education community, which includes those involved in generating textbooks, organizing courses and curricula, or the design, delivery, and funding of various public science programs, including PBS’s NOVA, the science education efforts of HHMI and other private foundations, and programs such as Science Friday on public radio, directly address the roots of racism, roots associated with biological processes such as the origins and maintenance of multicellularity and other forms of social organization among organisms, involved in coordinating their activities and establishing defenses against social cheaters and processes such as cancer, in an organismic context (1). These established defense mechanisms can, if not recognized and understood, morph into reflexive and unjustified intolerance, hostility toward, and persecution of various “distinguishable others.” I will consider both questions, albeit briefly, here.
Two factors have influenced my thinking about these questions. The first involves the design of the biofundamentals text/course and its extension to include topics in genetics (2). This involved thinking about what is commonly taught in genetics, what is critical for students to know going forward (and by implication what is not), and where materials on genetic processes best fit into a molecular biology curriculum (3). While engaged in such navel gazing there came an email from Malcolm Campbell describing student responses to the introduction of a chapter section on race and racism in his textbook Integrating Concepts in Biology. The various ideas of race, the origins of racism, and the periodic appearance of anti-immigrant, anti-religious and racist groups raise important questions – how best to clarify what is an undeniable observation, that different, isolated, sub-populations of a species can be distinguished from one another (see quote from Ernst Mayr’s 1994 “Typological versus Population thinking” →), from the deeper biological reality, that at the level of the individual these differences are meaningless. In what I think is an interesting way, the idea that people can be meaningfully categorized as different types of various platonic ideals (for example, as members of one race or the other) based on anatomical / linguistic differences between once distinct sub-populations of humans is similar to the dichotomy between common wisdom (e.g. that has influenced people’s working understanding of the motion of objects) and the counter-intuitive nature of empirically established scientific ideas (e.g. Newton’s laws and the implications of Einstein’s theory of general relativity). What appears on the surface to be true but in fact is not. In this specific case, there is a pressure toward what Mayr terms “typological” thinking, in which we class people into idealized (platonic) types or races (↓).
As pointed out most dramatically, and repeatedly, by Mayr (1985; 1994; 2000), and supported by the underlying commonality of molecular biological mechanisms and the continuity of life, stretching back to the last universal common ancestor, there are only individuals who are members of various populations that have experienced various degrees of separation from one another. In many cases, these populations have diverged and, through geographic, behavioral, and structure adaptations driven by natural, social, and sexual selection together with the effects of various events, some non-adaptive, such as bottlenecks, founder effects, and genetic drift, may eventually become reproductively isolated from one another, forming new species. An understanding of evolutionary principles and molecular mechanisms transforms biology from a study of non-existent types to a study of populations with their origins in common, sharing a single root – the last universal common ancestor (LUCA). Over the last ~200,000 years the movement of humans first within Africa and then across the planet has been impressive (→). These movements have been accompanied by the fragmentation of human populations. Campbell and Tishkoff (2008) identified 13 distinct ancestral African populations while Busby et al (2016) recognized 48 sub-saharan population groups. The fragmentation of the human population is being reversed (or rather rendered increasingly less informative) by the effects of migration and extensive intermingling (↓).
Ideas, such as race (and in a sense species), try to make sense of the diversity of the many different types of organisms we observe. They are based on a form of essentialist or typological thinking – thinking that different species and populations are completely different “kinds” of objects, rather than individuals in a population connected historically to all other living things. Race is a more pernicious version of this illusion, a pseudo-scientific, political and ideological idea that postulates that humans come in distinct, non-overlapping types (quote ↓ again, from Mayr). Such a weird idea underlies various illogical and often contradictory legal “rules” by which a person’s “race” is determined.
Given the reality of the individual and the unreality of race, racial profiling (see Satel,
2002) can lead to serious medical mistakes, as made clear in the essays by Acquaviva & Mintz (2010) “Are We Teaching Racial Profiling?”, Yudell et al (2016) “Taking Race out of Human Genetics”, and Donovan (2014) “The impact of the hidden curriculum”.
The idea of race as a type fails to recognize the dynamics of the genome over time. If possible (sadly not) a comparative analysis of the genome of a “living fossil”, such as modern day coelacanths and their ancestors (living more than 80 million years ago) would likely reveal dramatic changes in genomic DNA sequence. In this light the fact that between 100 to 200 new mutations are introduced into the human genome per generation (see Dolgin 2009 Human mutation rate revealed) seems like a useful number to be widely appreciated by students, not to mention the general public. Similarly, the genomic/genetic differences between humans, our primate relatives, and other mammals and the mechanisms behind them (Levchenko et al., 2017)(blog link) would seem worth considering and explicitly incorporating into curricula on genetics and human evolution.
While race may be meaningless, racism is not. How to understand racism? Is it some kind of political artifact, or does it arise from biological factors. Here, I believe, we find a important omission in many biology courses, textbooks, and curricula – namely an introduction and meaningful discussion of social evolutionary mechanisms. Many is the molecular/cell biology curriculum that completely ignores such evolutionary processes. Yet, the organisms that are the primary focus of biological research (and who pay for such research, e.g. humans) are social organisms at two levels. In multicellular organisms somatic cells, which specialize to form muscular, neural, circulatory and immune systems, bone and connective tissues, sacrifice their own inter-generational reproductive future to assist their germ line (sperm and/or eggs) relatives, the cells that give rise to the next generation of organisms, a form of inclusive fitness (Dugatkin, 2007). Moreover, humans are social organisms, often sacrificing themselves, sharing their resources, and showing kindness to other members of their group. This social cooperation is threatened by cheaters of various types (POST LINK). Unless these social cheaters are suppressed, by a range of mechanisms, and through processes of kin/group selection, multicellular organisms die and socially dysfunctional social populations are likely to die out. Without the willingness to cooperate, and when necessary, self-sacrifice, social organization is impossible – no bee hives, no civilizations. Imagine a human population composed solely of people who behave in a completely selfish manner, not honoring their promises or social obligations.
A key to social interactions involves recognizing those who are, and who are not part of your social group. A range of traits can serve as markers for social inclusion. A plausible hypothesis is that the explicit importance of group membership and defined social interactions becomes more critical when a society, or a part of society, is under stress. Within the context of social stratification, those in the less privileged groups may feel that the social contract has been broken or made a mockery of. The feeling (apparent reality) that members of “elite” or excessively privileged sub-groups are not willing to make sacrifices for others serves as evidence that social bonds are being broken (4). Times of economic and social disruption (migrations and conquests) can lead to increased explicit recognition of both group and non-group identification. The idea that outsiders (non-group members) threaten the group can feed racism, a justification for why non-group members should be treated differently from group members. From this position it is a small (conceptual) jump to the conclusion that non-group members are somehow less worthy, less smart, less trustworthy, less human – different in type from members of the group – many of these same points are made in an op-ed piece by Judis. 2018. What the Left Misses About Nationalism.
That economic or climatic stresses can foster the growth of racist ideas is no new idea; consider the unequal effects of various disruptions likely to be associated with the spread of automation (quote from George Will ↓) and the impact of climate change on migrations of groups within and between countries (see Saletan 2018b: Why Immigration Opponents Should Worry About Climate Change) are likely to spur various forms of social unrest, whether revolution or racism, or both – responses that could be difficult to avoid or control.
So back to the question of biology education – in this context understanding the ingrained responses of social creatures associated with social cohesion and integrity need to be explicitly presented. Similarly, variants of such mechanisms occur within multicellular organisms and how they work is critical to understanding how diseases such as cancer, one of the clearest forms of a cheater phenotype, are suppressed. Social evolutionary mechanisms provide the basis for understanding a range of phenomena, and the ingrained effects of social selection may be seen as one of the roots of racism, or at the very least a contributing factor worth acknowledging explicitly.
Thanks to Melanie Cooper and Paul Strode for comments. Minor edits 4 May 2019.
- It is an interesting possibility whether the 1%, or rather the super 0.1% represent their own unique form of social parasite, leading periodically to various revolutions – although sadly, new social parasites appear to re-emerge quite quickly.
- A part of the CoreBIO-biofundamentals project
- At this point it is worth noting that biofundamentals itself includes sections on social evolution, kin/group and sexual selection (see Klymkowsky et al., 2016; LibreText link).
- One might be forgiven for thinking that rich and privileged folk who escape paying what is seen as their fair share of taxes, might be cast as social cheaters (parasites) who, rather than encouraging racism might lead to revolutionary thoughts and actions.
Acquaviva & Mintz. (2010). Perspective: Are we teaching racial profiling? The dangers of subjective determinations of race and ethnicity in case presentations. Academic Medicine 85, 702-705.
Busby et al. (2016). Admixture into and within sub-Saharan Africa. Elife 5, e15266.
Campbell & Tishkoff. (2008). African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. Annu. Rev. Genomics Hum. Genet. 9, 403-433.
Donovan, B.M. (2014). Playing with fire? The impact of the hidden curriculum in school genetics on essentialist conceptions of race. Journal of Research in Science Teaching 51: 462-496.
Dugatkin, L. A. (2007). Inclusive fitness theory from Darwin to Hamilton. Genetics 176, 1375-1380.
Klymkowsky et al., (2016). The design and transformation of Biofundamentals: a non-survey introductory evolutionary and molecular biology course..” LSE Cell Biol Edu pii: ar70.
Levchenko et al., (2017). Human accelerated regions and other human-specific sequence variations in the context of evolution and their relevance for brain development. Genome biology and evolution 10, 166-188.
Mayr, E. (1985). The Growth of Biological Thought: Diversity, Evolution, and Inheritance. Cambridge, MA: Belknap Press of Harvard University Press.
Mayr, E. (1994). Typological versus population thinking. Conceptual issues in evolutionary biology, 157-160.
—- (2000). Darwin’s influence on modern thought. Scientific American 283, 78-83.
Satel, S. (2002). I am a racially profiling doctor. New York Times 5, 56-58.
Yudell et al., (2016). Taking race out of human genetics. Science 351, 564-565.
Pretty much everyone, at least in societies with access to public education or exposure to media in its various forms, has been introduced to the idea of the gene, but “exposure does not equate to understanding” (see Lanie et al., 2004). Here I will argue that part of the problem is that instruction in genetics (or in more modern terms, the molecular biology of the gene and its role in biological processes) has not kept up with the advances in our understanding of the molecular mechanisms underlying biological processes (Gayon, 2016).
Let us reflect (for a moment) on the development of the concept of a gene: Over the course of human history, those who have been paying attention to such things have noticed that organisms appear to come in “types”, what biologists refer to as species. At the same time, individual organisms of the same type are not identical to one another, they vary in various ways. Moreover, these differences can be passed from generation to generation, and by controlling which organisms were bred together; some of the resulting offspring often displayed more extreme versions of the “selected” traits. By strictly controlling which individuals were bred
together, over a number of generations, people were able to select for the specific traits they desired (→). As an interesting aside, as people domesticated animals, such as cows and goats, the availability of associated resources (e.g. milk) led to reciprocal effects – resulting in traits such as adult lactose tolerance (see Evolution of (adult) lactose tolerance & Gerbault et al., 2011). Overall, the process of plant and animal breeding is generally rather harsh (something that the fanciers of strange breeds who object to GMOs might reflect upon), in that individuals that did not display the desired trait(s) were generally destroyed (or at best, not allowed to breed).
Charles Darwin took inspiration from this process, substituting “natural” for artificial (human-determined) selection to shape populations, eventually generating new species (Darwin, 1859). Underlying such evolutionary processes was the presumption that traits, and their variation, was “encoded” in some type of “factors”, eventually known as genes and their variants, alleles. Genes influenced the organism’s molecular, cellular, and developmental systems, but the nature of these inheritable factors and the molecular trait building machines active in living systems was more or less completely obscure.
Through his studies on peas, Gregor Mendel was the first to clearly identify some of the rules for the behavior of these inheritable factors using highly stereotyped, and essentially discontinuous traits – a pea was either yellow or green, wrinkled or smooth. Such traits, while they exist in other organisms, are in fact rare – an example of how the scientific exploration of exceptional situations can help understand general processes, but the downside is the promulgation of the idea that genes and traits are somehow discontinuous – that a trait is yes/no, displayed by an organism or not – in contrast to the realities that the link between the two is complex, a reality rarely directly addressed (apparently) in most introductory genetics courses. Understanding such processes is critical to appreciating the fact that genetics is often not destiny, but rather alterations in probabilities (see Cooper et al., 2013). Without such an more nuanced and realistic understanding, it can be difficult to make sense of genetic information.
A gene is part of a molecular machine: A number of observations transformed the abstraction of Darwin’s and Mendel’s hereditary factors into physical entities and molecular mechanisms (1). In 1928 Fred Griffith demonstrated that a genetic trait could be transferred from dead to living organisms – implying a degree of physical / chemical stability; subsequent observations implied that the genetic information transferred involved DNA molecules. The determination of the structure of double-stranded DNA immediately suggested how information could be stored in DNA (in variations of bases along the length of the molecule) and how this information could be duplicated (based on the specificity of base pairing). Mutations could be understood as changes in the sequence of bases along a DNA molecule (introduced by chemicals, radiation, mistakes during replication, or molecular reorganizations associated with DNA repair mechanisms and selfish genetic elements.
But on their own, DNA molecules are inert – they have functions only within the context of a living organism (or highly artificial, that is man made, experimental systems). The next critical step was to understand how a gene works within a biological system, that is, within an organism. This involve appreciating the molecular mechanisms (primarily proteins) involved in identifying which stretches of a particular DNA molecule were used as templates for the synthesis of RNA molecules, which in turn could be used to direct the synthesis of polypeptides (see previous post on polypeptides and proteins). In the context of the introductory biology courses I am familiar with (please let me know if I am wrong), these processes are based on a rather deterministic context; a gene is either on or off in a particular cell type, leading to the presence or absence of a trait. Such a deterministic presentation ignores the stochastic nature of molecular level processes (see past post: Biology education in the light of single cell/molecule studies) and the dynamic interaction networks that underlie cellular behaviors.
But our level of resolution is changing rapidly (2). For a number of practical reasons, when the human genome was first sequence, the identification of polypeptide-encoding genes was based on recognizing “open-reading frames” (ORFs) encoding polypeptides of > 100 amino acids in length (> 300 base long coding sequence). The increasing sensitivity of mass spectrometry-based proteomic studies reveals that smaller ORFs (smORFs) are present and can lead to the synthesis of short (< 50 amino acid long) polypeptides (Chugunova et al., 2017; Couso, 2015). Typically an ORF was considered a single entity – basically one gene one ORF one polypeptide (3). A recent, rather surprising discovery is what are known as “alternative ORFs” or altORFs; these RNA molecules that use alternative reading frames to encode small polypeptides. Such altORFs can be located upstream, downstream, or within the previously identified conventional ORF
(figure →)(see Samandi et al., 2017). The implication, particularly for the analysis of how variations in genes link to traits, is that a change, a mutation or even the experimental deletion of a gene, a common approach in a range of experimental studies, can do much more than previously presumed – not only is the targeted ORF effected, but various altORFs can also be modified.
The situation is further complicated when the established rules of using RNAs to direct polypeptide synthesis via the process of translation, are violated, as occurs in what is known as “repeat-associated non-ATG (RAN)” polypeptide synthesis (see Cleary and Ranum, 2017). In this situation, the normal signal for the start of RNA-directed polypeptide synthesis, an AUG codon, is subverted – other RNA synthesis start sites are used leading to underlying or imbedded gene expression. This process has been found associated with a class of human genetic diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) characterized by the expansion of simple (repeated) DNA sequences (see Pattamatta et al., 2018). Once they exceed a certain length, such“repeat” regions have been found to be associated with the (apparently) inappropria
te transcription of RNA in both directions, that is using both DNA strands as templates (← A: normal situation, B: upon expansion of the repeat domain). These abnormal repeat region RNAs are translated via the RAN process to generate six different types of toxic polypeptides.
So what are the molecular factors that control the various types of altORF transcription and translation? In the case of ALS and FTD, it appears that other genes, and the polypeptides and proteins they encode, are involved in regulating the expression of repeat associated RNAs (Kramer et al., 2016)(Cheng et al., 2018). Similar or distinct mechanisms may be involved in other neurodegenerative diseases (Cavallieri et al., 2017).
So how should all of these molecular details (and it is likely that there are more to be discovered) influence how genes are presented to students? I would argue that DNA should be presented as a substrate upon which various molecular mechanisms occur; these include transcription in its various forms (directed and noisy), as well as DNA synthesis, modification, and repair mechanisms occur. Genes are not static objects, but key parts of dynamic systems. This may be one reason that classical genetics, that is genes presented within a simple Mendelian (gene to trait) framework, should be moved deeper into the curriculum, where students have the background in molecular mechanisms needed to appreciate its complexities, complexities that arise from the multiple molecular machines acting to access, modify, and use the information captured in DNA (through evolutionary processes), thereby placing the gene in a more realistic cellular perspective (4).
1. Described greater detail in biofundamentals™
2. For this discussion, I am completely ignoring the roles of genes that encode RNAs that, as far as is currently know, do not encode polypeptides. That said, as we go on, you will see that it is possible that some such non-coding RNA may encode small polypeptides.
3. I am ignoring the complexities associated with alternative promoter elements, introns, and the alternative and often cell-type specific regulated splicing of RNAs, to create multiple ORFs from a single gene.
4. With respects to Norm Pace – assuming that I have the handedness of the DNA molecules wrong or have exchanged Z for A or B.
- Cavallieri et al, 2017. C9ORF72 and parkinsonism: Weak link, innocent bystander, or central player in neurodegeneration? Journal of the neurological sciences 378, 49.
- Cheng et al, 2018. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nature communications 9, 51.
- Chugunova et al, 2017. Mining for small translated ORFs. Journal of proteome research 17, 1-11.
- Cleary & Ranum, 2017. New developments in RAN translation: insights from multiple diseases. Current opinion in genetics & development 44, 125-134.
- Cooper et al, 2013. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Human genetics 132, 1077-1130.
- Couso, 2015. Finding smORFs: getting closer. Genome biology 16, 189.
- Darwin, 1859. On the origin of species. London: John Murray.
- Gayon, 2016. From Mendel to epigenetics: History of genetics. Comptes rendus biologies 339, 225-230.
- Gerbault et al, 2011. Evolution of lactase persistence: an example of human niche construction. Philosophical Transactions of the Royal Society of London B: Biological Sciences 366, 863-877.
- Kramer et al, 2016. Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science 353, 708-712.
- Lanie et al, 2004. Exploring the public understanding of basic genetic concepts. Journal of genetic counseling 13, 305-320.
- Pattamatta et al, 2018. All in the Family: Repeats and ALS/FTD. Trends in neurosciences 41, 247-250.
- Samandi et al, 2017. Deep transcriptome annotation enables the discovery and functional characterization of cryptic small proteins. Elife 6.
In the context of public discourse, there are times when one is driven to simple, reflexive and often disproportionate (exasperated) responses. That happens to me whenever people talk about the various theories that they apply to a process or event. I respond by saying (increasingly silently to myself), that what they mean is really that they have an idea, a model, a guess, a speculation, or a comforting “just-so” story. All too often such competing “theories” are flexible enough to explain (or explain away) anything, depending upon one’s predilections. So why a post on theories? Certainly the point as been made before (see Ghose. 2013. “Just a Theory”: 7 Misused Science Words“). Basically because the misuse of the term theory, whether by non-scientists, scientists, or science popularizers, undermines understanding of, and respect for the products of the scientific enterprise. It confuses hard won knowledge with what are often superficial (or self-serving) opinions. When professors, politicians, pundits, PR flacks, or regular people use the word theory, they are all too often, whether consciously or not, seeking to elevate their ideas through the authority of science.
So what is the big deal anyway, why be an annoying pain in the ass (see Christopher DiCarlo’s video), challenging people, making them uncomfortable, and making a big deal about something so trivial. But is it really trivial? I think not, although it may well be futile or quixotic. The inappropriate use of the word theory, particularly by academics, is an implicit attempt to gain credibility. It is also an attack on the integrity of science. Why? Because like it or not, science is the most powerful method we have to understand how the world works, as opposed to what the world or our existence within the world means. The scientific enterprise, abiding as it does by explicit rules of integrity, objective evidence, logical and quantifiable implications, and their testing has been a progressive social activity, leading to useful knowledge – knowledge that has eradicated small pox and polio (almost) and produced iPhones, genetically modified organisms, and nuclear weapons. That is not to say that the authority of science has not been repeatedly been used to justify horrific sociopolitical ideas, but those ideas have not been based on critically evaluated and tested scientific theories, but on variously baked ideas that claim the support of science (both the eugenics and anti-vaccination movements are examples).
Modern science is based on theories, ideas about the universe that explain and predict what we will find when we look (smell, hear, touch) carefully at the world around us. And these theories are rigorously and continually tested, quantitatively – in fact one might say that the ability to translate a theory into a quantitative prediction is one critical hallmark of a real versus an ersatz (non-scientific) theory [here is a really clever approach to teaching students about facts and theories, from David Westmoreland]
So where do (scientific) theories come from? Initially they are guesses about how the world works, as stated by Richard Feynman and the non-scientific nature of vague “theories”. Guesses that have evolved based on testing, confirmation, and where wrong – replacement with more and more accurate, logically well constructed and more widely applicable constructs – an example of the evolution of scientific knowledge. That is why ideas are cheap, they never had, or do not develop the disciplinary rigor necessary to become a theory. In fact, it often does not even matter, not really, to the people propounding these ideas whether they correspond to reality at all, as witness the stream of tweets from various politicians or the ease with which many apocalyptic predictions are replaced when they turn out to be incorrect. But how is the average person to identify the difference between a (more or less half-baked) idea and a scientific theory? Probably the easiest way is to ask, is the idea constantly being challenged, validated, and where necessary refined by both its proponents and its detractors. One of the most impressive aspects of Einstein’s theory of general relativity is the accuracy of its predictions (the orbit of Mercury, time-dilation, and gravitational waves (link)), predictions that if not confirmed would have forced its abandonment – or at the very least serious revision. It is this constant application of a theory, and the rigorous testing of its predictions (if this, then that) that proves its worth.
Another aspect of a scientific theory is whether it is fecund or sterile. Does its application lead to new observations that it can explain? In contrast, most ideas are dead ends. Consider the recent paper on the possibility that life arose outside of the Earth, a proposal known as pan-spermia (1) – “a very plausible conclusion – life may have been seeded here on Earth by life-bearing comets” – and recently tunneling into the web’s consciousness in stories implying the extra-terrestrial origins of cephalopods (see “no, octopuses don’t come from outer space.”) Unfortunately, no actual biological insights emerge from this idea (wild speculation), since it simply displaces the problem, if life did not arise here, how did it arise elsewhere? If such ideas are embraced, as is the case with many religious ideas, their alteration often leads to violent schism rather than peaceful refinement. Consider, as an example, an idea had by an archaic Greek or two that the world was made of atoms. These speculations were not theories, since their implications were not rigorously tested. The modern atomic theory has been evolving since its introduction by Dalton, and displays the diagnostic traits of a scientific theory. Once introduced to explain the physical properties of matter, it led to new discoveries and explanations for the composition and structure of atoms themselves (electrons, neutrons, and protons), and then to the composition and properties of these objects, quarks and such (link to a great example.)
Scientific theories are, by necessity, tentative (again, as noted by Feynman) – they are constrained and propelled by new and more accurate observations. A new observation can break a theory, leading it to be fixed or discarded. When that happens, the new theory explains (predicts) all that the old theory did and more. This is where discipline comes in; theories must meet strict standards – the result is that generally there cannot be two equivalent theories that explain the same phenomena – one (or both) must be wrong in some important ways. There is no alternative, non-atomic theory that explains the properties of matter.
The assumption is that two “competing” theories will make distinctly different predictions, if we look (and measure) carefully enough. There are rare cases where two “theories” make the same predictions; the classic example is the Ptolemaic Sun-centered and the Copernican Earth-centered models of the solar system. Both explained the appearances of planetary motion more or less equally well, and so on that basis there was really no objective reason to choose between them. In part, this situation arose from an unnecessary assumption underlying both models, namely that celestial objects moved in perfect circular orbits – this assumption necessitated the presence of multiple “epicycles” in both models. The real advance came with Kepler’s recognition that celestial objects need not travel in perfect circular orbits, but rather in elliptical orbits; this liberated models of the solar system from the need for epicycles. The result was the replacement of “theories of solar system movement” with a theory of planetary/solar/galactic motions”.
Whether, at the end of the day scientific theories are comforting or upsetting, beautiful or ugly remains to be seen, but what is critical is that we defend the integrity of science and call out the non-scientific use of the word theory, or blame ourselve for the further decay of civilization (perhaps I am being somewhat hyperbolic – sorry).
1. Although really, pan-oogenia would be better. Sperm can do nothing without an egg, but an unfertilized egg can develop into an organism, as occurs with bees.